This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The long term goal of the work in my laboratory is to understand the multiple roles that the Notch signaling pathway plays during embryonic development in mammals, and the connections between this pathway and the development of congenital human disease syndromes. The components of the Notch signaling pathway constitute an evolutionarily-conserved set of proteins that controls cell fate specification in numerous tissues, and is essential for proper embryonic development in organisms as diverse as insects, nematodes and mammals. In Drosophila, the Notch gene encodes a large transmembrane receptor that, at the extracellular surface of a cell, interacts with membrane-bound ligands encoded by the Delta and Serrate genes. In mammals, four Notch family receptors have been described: Notch1, 2, 3 and 4. Five genes encoding ligands for the Notch family of receptors have been described: two of the Jagged/Serrate family (Jag1 and Jag2) and three of the Delta-like family (Dll1, Dll3 and Dll4). While previous work has revealed a role for Notch signaling in regulating myogenesis and skeletal muscle satellite cell activation, no progressive Notch signaling-dependent myopathy model has been described. We have found that mice doubly heterozygous for mutations of the Notch ligands Dll1 and Jag2 (Dll1/Jag2 +/- mice) exhibit a progressive postnatal myopathy that preferentially affects epaxial muscles of the back. This model provides a valuable new resource for studying the physiological role of Notch signaling during skeletal muscle function in mammals.